N-Carbamoylmethyl-4-(R)-Phenyl-2-Pyrrolidinone, Method of its Preparation and Pharmaceutical Use

ABSTRACT

The invention relates to the R-enantiomer of N-carbamoylmethyl-4-phenyl-2-pyrrolidinone (R-Carphedon) of pharmacological value. The method of its preparation includes the N-alkylation of 4(R)-phenyl-2-pyrrolidinone with ethyl bromoacetate in the presence of a strong base and the treatment of intermediate N-ethoxycarbonylmethyl-4(R)-phenyl-2-pyrrolidinone with ammonia.

BACKGROUND OF THE INVENTION

The invention relates to the discovery of the biologically activeR-enantiomer of N-carbamoylmethyl-4-aryl-2-pyrrolidinone and easy andeffective method of its preparation.

It is known that humans in a stress situation or under psycho-emotionalstrain exhibit irrational and inadequate forms of behavior, disorders ofmental capacity, declined speed of reaction, and increased number oferroneous decisions etc.

Therefore discovery of pharmaceuticals abating and preventing the effectof a stress factor is of substantial importance. For this purpose thenootropic GABA derivatives: Phenibut and Baclofen are applied, eventhough their use is followed by drowsiness, depression, dizziness,lowered psychomotor reactions etc.

In comparison to GABA derivatives another agent widely used for thispurpose N-carbamoylmethyl-4-aryl-2-pyrrolidinone (Carphedon, INN) couldbe regarded as a much more perspective psycho-stimulator due to the lesspronounced side effects.

The R- and S-enantiomeric forms of Carphedon and their pharmacologicproperties are not known. The pharmacologic properties of only theracemic Carphedon are published today and there is no data concerningpossible differences of pharmacological properties for its separate R-and S-enantiomers. The absence of this highly important information alsodoes not allow to adequately estimate the real pharmaceutical potentialof Carphedon already used in medicine, because in reality it isrepresented by a mixture of R- and S-enantiomers, which may exhibitdifferent pharmacologic properties.

In the present invention we have developed methods for preparation ofpure R- and S-Carphedon and unexpectedly discovered that R-Carphedon asan antidepressant, analgesic, muscle relaxant and psycho-stimulatingcompound is more effective than the racemic Carphedon or S-Carphedon.

SUMMARY AND DETAILED DESCRIPTION

The invention relates to the R-enantiomer of4-phenyl-1-pyrrolidineacetic acid amide. More particularly, theinvention relates to N-carbamoylmethyl-4(R)-phenyl-2-pyrrolidinone ofthe formula:

a new chemical compound of pharmacological value and a method of itsproduction.

DETAILED DESCRIPTION OF THE INVENTION

As we have discovered, the preparation of R-Carphedon 4 the same asS-Carphedon 4a can be easily achieved by the means of the N-alkylationof available 4(R)-phenyl-2-pyrrolidinone (1) or4(S)-phenyl-2-pyrrolidinone (1a) with ethyl bromoacetate (2) in thepresence of a strong base and by the following transformation ofethoxycarbonyl group in the intermediate 2-pyrrolidinones 3 and 3a intocarbamoyl function by the treatment with ammonia.

Following examples illustrate the synthetic part of invention.

Example 1 N-Carbamoylmethyl-4(R)-phenyl-2-pyrrolidinone (4)

The solution of 4(R)-phenyl-2-pyrrolidinone (1) (345 mg, 2.14 mM) in1,4-dioxane (30 ml) was added to the suspension of sodium hydride (56mg, 2.35 mM) in 1,4-dioxane (30 ml). The mixture was heated at 80÷90° C.during 30 min and then cooled to room temperature. Ethyl bromoacetate(393 mg, 2.37 mM) was added and the reaction mixture was refluxed at110÷120° C. for 6 hours. Obtained mixture was concentrated under reducedpressure. Residue was purified by column chromatography on silicagelwith ethylacetate-hexane mixture 1:1, givingN-ethoxycarbonylmethyl-4(R)-phenyl-2-pyrrolidinone (3) (338 mg, 64%).[α]_(D) ²⁰+4.60° (c=3, MeOH). ¹H NMR (CDCl₃), δ: 1.28 (3H, t, CH₂ CH ₃);2.59 (1H, d, d, 3-CH₂); 2.87 (1H, d, d, 3-CH₂); 3.54 (1H, t, 5-CH₂);3.64 (1H, quintet, 4-CH); 3.83 (1H, t, 5-CH₂); 4.11 (2H, s, NCH₂CO);4.20 (2H, q, CH ₂CH₃); 7.20-7.39 (5H, m, C₆H₅).

The solution of N-ethoxycarbonylmethyl-4(R)-phenyl-2-pyrrolidinone (3)(250 mg, 1.01 mM) in methanol (30 ml) saturated by stream of gaseousammonia for 5 hours. Reaction mixture was concentrated under reducedpressure and the residue was purified by column chromatography withethylacetate-hexane mixture 1:1 silicagel givingN-carbamoylmethyl-4(R)-phenyl-2-pyrrolidinone (4a) (187 mg, 85%). M.p.107.5-108° C. [α]_(D) ²⁰=+8.5° (c=3, MeOH). ¹H NMR (CDCl₃), δ: 2.61 (1H,d, d, 3-CH₂); 2.87 (1H, d, d, 3-CH₂); 3.54 (1H, t, 5-CH₂); 3.66 (1H,quintet, 4-CH); 3.89 (1H, t, 5-CH₂); 4.00 (2H, s, NCH₂CO); 5.68 and 6.21(1H and 1H, br.s and br.s, NH₂); 7.20-7.40 (5H, m, C₆H₅).

Example 2 N-Carbamoylmethyl-4(S)-phenyl-2-pyrrolidinone (4a)

Substituting pyrrolidinone 1 in Example 1 by 4(S)-phenyl-2-pyrrolidinone(1a) S-enantiomeric N-carbamoylmethyl-4(S)-phenyl-2-pyrrolidinone (4a)was obtained. [α]_(D) ²⁰=−8.3° (c=3, MeOH). ¹H NMR (CDCl₃), δ: 2.61 (1H,d, d, 3-CH₂); 2.87 (1H, d, d, 3-CH₂); 3.54 (1H, t, 5-CH₂); 3.66 (1H,quintet, 4-CH); 3.89 (1H, t, 5-CH₂); 4.00 (2H, s, NCH₂CO); 5.68 and 6.21(1H and 1H, br.s and br.s, NH₂); 7.20-7.40 (5H, m, C₆H₅).

According to the invention, we have performed the comparativeinvestigation of antidepressant, muscle relaxant, locomotor andanalgesic activities for R- and S-enantiomers ofN-carbamoylmethyl-4-aryl-2-pyrrolidinone and compared with those of theracemic one (Carphedon) (Table 1-3). We have unexpectedly discovered,that R-Carphedon possesses more pronounced desired pharmacologicalproperties comparing with S-Carphedon.

The data presented in Table 1 demonstrate an excellent antidepressantactivity of R-enantiomer of Carphedon using the standard Porsolt forcedswim test (FST). After the preliminary treatment with R-Carphedonl, theanimals did not spent any time immobile. Also in the case of animalstreated with racemic Carphedon, the immobility period was significantlyshorter. Contrary to that, mice in the control and S-Carphedon groupsdemonstrated characteristic behavior for FST test conditions registeredas an immobilization in response to stress factor.

Similar advantage of R-Carphedon in comparison to S-Carphedon andracemate was observed in experiments characterizing the motor activityof mice in the standard open field test (Table 2). The i.p.administration of the test compounds in equal 50 mg/kg doses causedprolonged and stable increase in animal activity in the case ofR-Carphedon, which at the end of the 120 min observation period wasabout two times higher than activity caused by S-Carphedonl.

The data presented in Table 3 show that equal muscle relaxant activityand analgesic effect of tested compounds was achieved by the lowerdosages of R-Carphedon than the same of S-Carphedon.

TABLE 1 Antidepressant properties of test compounds according toPorsolt* forced swim test (FST)** Test substance Immobilization time,sec* Control 215 ± 10  Carphedon   35 ± 12^(##) R-Carphedon 0^(##)S-Carphedon 110 ± 12^(#) *R. D. Porsolt, et. al., Arch. Intern.Pharmacodynamie, 1977, vol. 229, p. 327-336 **i.p. administration ofcompounds 1 hour before the test in male ICR mice in the dosage of 100mg/kg ^(#)P > 0.05 vs control ^(##)P > 0.001 vs control

TABLE 2 Characteristics of locomotor activity* after i.p. administrationof tested compounds in male ICR mice in dosage of 50 mg/kg* TestHorizontal activity counts (min) Vertical activity counts (min)Exploratory activity counts (min) substance 30 60 120 30 60 120 30 60120 Control  47.3 ± 2.1  25.5 ± 1.7  21.6 ± 1.8 10.3 ± 1.1  7.5 ± 0.9 4.1 ± 0.7  18.7 ± 1.9 16.8 ± 1.8 11.3 ± 1.3 Carphedon 72.3^(#) ± 6.0 61.4^(#) ± 6.7 49.4^(#) ± 5.8 12.3 ± 4.0 10.9 ± 2.5  7.9 ± 2.0  14.8 ±3.0 19.1 ± 4.8 17.8 ± 2.8 R-Carphedon 77.9^(#) ± 5.7  80.4^(#) ± 6.578.4^(#) ± 7.1 10.0 ± 1.5 12.5 ± 3.2 11.6 ± 4.0  15.5 ± 2.9 16.4 ± 3.617.8 ± 4.7 S-Carphedon  56.3 ± 5.7  43.3^(#) ± 6.6  36.4 ± 7.1  7.0 ±1.6  7.0 ± 2.8  4.9 ± 1.7  5.5^(#) ± 1.5  7.8 ± 4.2 11.5 ± 2.8 ^(*)M. L.Weischer, Psychopharmacology 1976; 50; 275 ^(#)P < 0.05 ANOVA testfollowed Studen's t-test

TABLE 3 Effective dosages of test compounds responsible for the samemuscle relaxant activity¹ and analgesic effect² in male ICR mice. ED₅₀(mg/kg)* Test Muscle relaxant activity Analgesic effect substanceChimney test Traction Rota rod Hot plate R-Carphedon 199 ± 38 456 ± 122193 ± 26 10 ± 42 S-Carphedon 286 ± 78 548 ± 75  459 ± 87 50 ± 63 *i.p.administration in dosages 50; 100; 250 and 500 mg/kg ¹N. W. Dunham, et.al, J. Am. Pharm. Assoc., 46: 208, 1957. ²N. B. Eddy, D. Leimbach, J.Pharmacol. Experimental Therapy, 1953, vol. 107, N 3, p. 358-393.

The obtained results prove the high therapeutic value for R-Carphedonexceeding the same one for racemic Carphedon, because pharmaceuticalproperties of the latter are negatively affected by the presence ofS-Carphedon, which characterizes by lower and in some experiments byconsiderably weaker activity.

1. A method of treating or preventing a condition in a patient in needthereof which comprises: selecting a patient; and administering apharmaceutical composition to the patient, wherein the pharmaceuticalcomposition comprises a therapeutically effective amount of pureN-carbamoylmethyl-4(R)-phenyl-2-pyrrolidinone (I), separate from theS-enantiomer:

wherein * marks chiral carbon atom, further wherein the condition isselected from the group consisting of stress, drowsiness, depression,dizziness, lowered psychomotor reactions, disorders of mental capacity,delayed speed of reaction, increased number of erroneous decisions,pain, muscle hypertonicity, and combinations thereof.
 2. The method ofclaim 1, wherein the therapeutically effective amount of pureN-carbamoylmethyl-4(R)-phenyl-2-pyrrolidinone (I), separate from theS-enantiomer administered is selected from the group consisting of about50, about 100, about 250, and about 500 mg/kg body weight.
 3. The methodof claim 1, wherein the pharmaceutical composition has an effectselected from the group consisting of an antidepressant effect, astress-protective effect, a modulator of locomotor activity effect, amuscle relaxant effect, an analgesic effect, a psycho-stimulatingeffect, a nootropic effect, and combinations thereof.
 4. The method ofclaim 1, wherein the pharmaceutical composition comprises at least onepharmaceutically acceptable excipient.
 5. A method of administering apharmaceutical composition to a patient in need thereof which comprises:selecting a patient; and administering a pharmaceutical composition tothe patient, wherein the pharmaceutical composition comprises atherapeutically effective amount of pureN-carbamoylmethyl-4(R)-phenyl-2-pyrrolidinone (I), separate from theS-enantiomer:

wherein * marks chiral carbon atom, wherein the pharmaceuticalcomposition has an effect selected from the group consisting of anantidepressant effect, a stress-protective effect, a modulator oflocomotor activity effect, a muscle relaxant effect, an analgesiceffect, a psycho-stimulating effect, a nootropic effect, andcombinations thereof.
 6. The method of claim 5, wherein thetherapeutically effective amount of pureN-carbamoylmethyl-4(R)-phenyl-2-pyrrolidinone (I), separate from theS-enantiomer administered is selected from the group consisting of about50, about 100, about 250, and about 500 mg/kg body weight.
 7. The methodof claim 5, wherein the therapeutically effective amount of pureN-carbamoylmethyl-4(R)-phenyl-2-pyrrolidinone (I), separate from theS-enantiomer treats or prevents a condition selected from the groupconsisting of stress, drowsiness, depression, dizziness, loweredpsychomotor reactions, disorders of mental capacity, delayed speed ofreaction, increased number of erroneous decisions, pain, musclehypertonicity, and combinations thereof.
 8. The method of claim 5,wherein the pharmaceutical composition comprises at least onepharmaceutically acceptable excipient.